Adapting IAPT services to support frontline NHS staff during the Covid-19 pandemic: the Homerton Covid Psychological Support (HCPS) pathway.

The Coronavirus (Covid-19) pandemic is exerting unprecedented pressure on NHS Health and Social Care provisions, with frontline staff, such as those of critical care units, encountering vast practical and emotional challenges on a daily basis. Although staff are being supported through organisational provisions, facilitated by those in leadership roles, the emergence of mental health difficulties or the exacerbation of existing ones amongst these members of staff is a cause for concern. Acknowledging this, academics and healthcare professionals alike are calling for psychological support for frontline staff, which not only addresses distress during the initial phases of the outbreak but also over the months, if not years, that follow. Fortunately, mental health services and psychology professional bodies across the United Kingdom have issued guidance to meet these needs. An attempt has been made to translate these sets of guidance into clinical provisions via the recently established Homerton Covid Psychological Support (HCPS) pathway delivered by Talk Changes (Hackney & City IAPT). This article describes the phased, stepped-care and evidence-based approach that has been adopted by the service to support local frontline NHS staff. We wish to share our service design and pathway of care with other Improving Access to Psychological Therapies (IAPT) services who may also seek to support hospital frontline staff within their associated NHS Trusts and in doing so, lay the foundations of a coordinated response. KEY LEARNING AIMS: (1)To understand the ways staff can be psychologically and emotionally impacted by working on the frontline of disease outbreaks.(2)To understand the ways in which IAPT services have previously supported populations exposed to crises.(3)To learn ways of delivering psychological support and interventions during a pandemic context based on existing guidance and research.

Facilitating mental health research for patients, clinicians and researchers: a mixed-method study.

OBJECTIVES: Research registers using Consent for Contact (C4C) can facilitate recruitment into mental health research studies, allowing investigators to contact patients based on clinical records information. We investigated whether such a register was useful for mental health research, seeking the perspectives of patients and research investigators. SETTING AND DESIGN: In 2012, a C4C register was developed in a large secondary mental health provider within the UK; almost 9000 patients have joined. This mixed-method study audited the effectiveness of the register. PARTICIPANTS: A 'mystery shopper' exercise was conducted, and patients (n=21) were recruited to ask clinicians about the availability of research opportunities. Structured interviews were conducted with patients (n=52) about their experiences of being on the register. Similar interviews were conducted with 18 investigators from 19 studies, who had attempted to use the register to recruit participants. OUTCOME MEASURES: The impact of C4C on study recruitment, and whether it helped patients learn about research. RESULTS: So far, the register has provided 928 individuals with 1085 research opportunities (in 60% of cases, the individual agreed to participate in the study). Clinicians were willing to link patients to research opportunities, but often lacked information about studies. For patients, the register provided opportunities which they may not otherwise have; 27 of 52 had participated in studies since joining the register (18 participating for the first time). Most investigators used the register to supplement recruitment to their studies, but described problems in prescreening potential participants from a clinical record for complex studies. CONCLUSIONS: Although the register helped investigators recruit for studies, and provided patients with research opportunities, clinicians' input is still useful for identifying suitable participants. C4C registers should be adapted to provide clinicians with automatically updated information on local studies allowing them to match patients on their caseload with active studies.

Antimicrobial resistance in eight US hospitals along the US-Mexico border, 2000-2006.

Antimicrobial resistance (AR) is a growing problem worldwide and international travel, cross-border migration, and antimicrobial use may contribute to the introduction or emergence of AR. We examined AR rates and trends along the US-Mexico border by analysing microbiology data from eight US hospitals in three states bordering Mexico. Microbiology data were ascertained for the years 2000-2006 and for select healthcare and community pathogens including, three Gram-negative (Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae) and three Gram-positive (Staphylococcus aureus, Enterococcus, Streptococcus pneumoniae) pathogens and 10 antimicrobial-pathogen combinations. Resistance was highest in S. aureus (oxacillin resistance 45·7%), P. aeruginosa (quinolone resistance 22·3%), and E. coli (quinolone resistance 15·6%); six (60%) of the 10 antimicrobial-pathogen combinations studied had a significantly increasing trend in resistance over the study period. Potential contributing factors in the hospital and community such as infection control practices and antimicrobial use (prescription and non-prescription) should be explored further in the US-Mexico border region.

Prevention and control of rabies in an age of global travel: a review of travel- and trade-associated rabies events--United States, 1986-2012.

Rabies prevention and control efforts have been successful in reducing or eliminating virus circulation regionally through vaccination of specific reservoir populations. A notable example of this success is the elimination of canine rabies virus variant from the United States and many other countries. However, increased international travel and trade can pose risks for rapid, long-distance movements of ill or infected persons or animals. Such travel and trade can result in human exposures to rabies virus during travel or transit and could contribute to the re-introduction of canine rabies variant or transmission of other viral variants among animal host populations. We present a review of travel- and trade-associated rabies events that highlight international public health obligations and collaborative opportunities for rabies prevention and control in an age of global travel. Rabies is a fatal disease that warrants proactive coordination among international public health and travel industry partners (such as travel agents, tour companies and airlines) to protect human lives and to prevent the movement of viral variants among host populations.

Binational outbreak of Guillain-Barré syndrome associated with Campylobacter jejuni infection, Mexico and USA, 2011.

In June 2011, a cluster of suspected cases of Guillain-Barré syndrome (GBS), which can follow Campylobacter jejuni infection, was identified in San Luis Río Colorado (SLRC), Sonora, Mexico and Yuma County, Arizona, USA. An outbreak investigation identified 26 patients (18 from Sonora, eight from Arizona) with onset of GBS 4 May-21 July 2011, exceeding the expected number of cases (n = 1-2). Twenty-one (81%) patients reported antecedent diarrhoea, and 61% of 18 patients tested were seropositive for C. jejuni IgM antibodies. In a case-control study matched on age group, sex, ethnicity, and neighbourhood of residence, all Arizona GBS patients travelled to SLRC during the exposure period vs. 45% of matched controls (matched odds ratio 8·1, 95% confidence interval 1·5-∞). Exposure information and an environmental assessment suggested that GBS cases resulted from a large outbreak of C. jejuni infection from inadequately disinfected tap water in SLRC. Binational collaboration was essential in investigating this cross-border GBS outbreak, the first in mainland North America since 1976.

Influenza-like illness surveillance on the California-Mexico border, 2004-2009.

BACKGROUND: Since 2004, the Naval Health Research Center, with San Diego and Imperial counties, has collaborated with the US Centers for Disease Control and Prevention to conduct respiratory disease surveillance in the US-Mexico border region. In 2007, the Secretariat of Health, Mexico and the Institute of Public Health of Baja California joined the collaboration. OBJECTIVES: The identification of circulating respiratory pathogens in respiratory specimens from patients with influenza-like illness (ILI). METHODS: Demographic, symptom information and respiratory swabs were collected from enrollees who met the case definition for ILI. Specimens underwent PCR testing and culture in virology and bacteriology. RESULTS: From 2004 through 2009, 1855 persons were sampled. Overall, 36% of the participants had a pathogen identified. The most frequent pathogen was influenza (25%), with those aged 6-15 years the most frequently affected. In April 2009, a young female participant from Imperial County, California, was among the first documented cases of 2009 H1N1. Additional pathogens included influenza B, adenovirus, parainfluenza virus, respiratory syncytial virus, enterovirus, herpes simplex virus, Streptococcus pneumoniae, and Streptococcus pyogenes. CONCLUSIONS: The US-Mexico border is one of the busiest in the world, with a large number of daily crossings. Due to its traffic, this area is an ideal location for surveillance sites. We identified a pathogen in 36% of the specimens tested, with influenza A the most common pathogen. A number of other viral and bacterial respiratory pathogens were identified. An understanding of the incidence of respiratory pathogens in border populations is useful for development of regional vaccination and disease prevention responses.

Expression profiling reveals functionally important genes and coordinately regulated signaling pathway genes during in vitro angiogenesis.

Angiogenesis is a complex multicellular process requiring the orchestration of many events including migration, alignment, proliferation, lumen formation, remodeling, and maturation. Such complexity indicates that not only individual genes but also entire signaling pathways will be crucial in angiogenesis. To define an angiogenic blueprint of regulated genes, we utilized our well-characterized three-dimensional collagen gel model of in vitro angiogenesis, in which the majority of cells synchronously progress through defined morphological stages culminating in the formation of capillary tubes. We developed a comprehensive three-tiered approach using microarray analysis, which allowed us to identify genes known to be involved in angiogenesis and genes hitherto unlinked to angiogenesis as well as novel genes and has proven especially useful for genes where the magnitude of change is small. Of interest is the ability to recognize complete signaling pathways that are regulated and genes clustering into ontological groups implicating the functional importance of particular processes. We have shown that consecutive members of the mitogen-activated protein kinase and leukemia inhibitory factor signaling pathways are altered at the mRNA level during in vitro angiogenesis. Thus, at least for the mitogen-activated protein kinase pathway, mRNA changes as well as the phosphorylation changes of these gene products may be important in the control of blood vessel morphogenesis. Furthermore, in this study, we demonstrated the power of virtual Northern blot analysis, as an alternative to quantitative RT-PCR, for measuring the magnitudes of differential gene expression.

Antibodies raised against the second extracellular loop of the human muscarinic M3 receptor mimic functional autoantibodies in Sjögren's syndrome.

Functional antimuscarinic M3 receptor (M3R) autoantibodies have been shown to inhibit cholinergic neurotransmission at the postsynaptic level and appear to mediate parasympathetic dysfunction, including sicca symptoms in Sjögren's syndrome (SS). The precise epitope(s) involved in the inhibition of M3R-mediated cholinergic neurotransmission has not been defined. In this study, an active immunization approach to raise antibodies with functional activity against the second extracellular loop of the M3R was used and their functional properties were compared with those of human autoantibodies. Peptides corresponding to the second extracellular loop of the M3R were used as immunogens in rabbits, and antisera were tested for inhibition of carbachol-evoked colon smooth muscle contraction in parallel with immunoglobulin G from a patient with SS. Anti-M3R antibodies were affinity purified on a peptide representing a dominant functional epitope at the COOH terminus of the second extracellular loop of the M3R and tested for concentration-dependent inhibition. Experimentally raised anti-M3R antibodies, like the human autoantibodies, showed concentration-dependent and noncompetitive inhibition of carbachol-evoked colon contractions. Inhibitory activity was detected by functional assays at concentrations as low as 3 ng/ml, which was below the threshold of detection of antibody by peptide enzyme-linked immunosorbent assay. It is concluded that the experimentally raised anti-M3R antibodies share the functional properties of autoantibodies in patients with SS.

Subcellular distribution of aquaporin 5 in salivary glands in primary Sjögren's syndrome.

Secretions from salivary and lacrimal glands are reduced in patients with primary Sjögren's syndrome (PSS). Since aquaporin 5 is involved in transport of water and is present in salivary and lacrimal glands, this protein was thought to have a major role in the pathogenesis of PSS. We used indirect immunofluorescence and an immunoperoxidase technique to assess expression and subcellular localisation of aquaporin 5 in patients and controls. Our results suggest that the distribution and density of aquaporin 5 in salivary glands does not differ between patients with PSS and those without. Thus, the role of aquaporin 5 in the pathogenesis of PSS needs to be reassessed and alternative pathogenetic mechanisms investigated.

Autonomic dysfunction in Lambert-Eaton myasthenic syndrome.

Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disorder characterized by muscle weakness and autonomic dysfunction. Recent ex vivo and in vitro studies demonstrate that autoantibodies to the P/Q-subtype of voltage-gated calcium channel inhibit transmitter release from parasympathetic, sympathetic, and enteric neurons, a mechanism likely to underlie the widespread autonomic dysfunction in LEMS. This review summarizes clinical studies characterizing the autonomic symptoms and signs in LEMS and the effectiveness of treatment in alleviating these symptoms. Serological assays and in vitro pharmacologic and electrophysiologic studies are also discussed.

Remodelling of the actin cytoskeleton is essential for replication of intravacuolar Salmonella.

Maturation and maintenance of the intracellular vacuole in which Salmonella replicates is controlled by virulence proteins including the type III secretion system encoded by Salmonella pathogenicity island 2 (SPI-2). Here, we show that, several hours after bacterial uptake into different host cell types, Salmonella induces the formation of an F-actin meshwork around bacterial vacuoles. This structure is assembled de novo from the cellular G-actin pool in close proximity to the Salmonella vacuolar membrane. We demonstrate that the phenomenon does not require the Inv/Spa type III secretion system or cognate effector proteins, which induce actin polymerization during bacterial invasion, but does require a functional SPI-2 type III secretion system, which plays an important role in intracellular replication and systemic infection in mice. Treatment with actin-depolymerizing agents significantly inhibited intramacrophage replication of wild-type Salmonella typhimurium. Furthermore, after this treatment, wild-type bacteria were released into the host cell cytoplasm, whereas SPI-2 mutant bacteria remained within vacuoles. We conclude that actin assembly plays an important role in the establishment of an intracellular niche that sustains bacterial growth.

Two-generation reproduction studies in Rats fed di-isodecyl phthalate.

Di-isodecyl phthalate (DIDP) is a commercial plasticizer with low toxicity in many animal studies. The effects of dietary DIDP administration on fertility and developmental parameters were assessed in Sprague-Dawley rats utilizing two generation reproductive toxicity studies generally consistent with current regulatory guidelines. Dietary levels ranged from 0.02 to 0.8% (or approximately 15 to 600 mg/kg/day). In the reproductive studies, there were no effects on fertility, but there were decreases in adult body weight along with corresponding increases in liver and kidney weights and histopathologic changes indicative of peroxisomal proliferation. There were no effects on live birth index, but reduced offspring survival was observed at postnatal days 1 to 4. This reduced survival was more pronounced in the F2 generation in which statistical significance was achieved at levels of 0.2% DIDP and greater. There were also transient decreases in offspring body weights prior to weaning, corresponding to rapid offspring growth, and high levels of food consumption. There were no notable alterations in developmental landmarks. Overall, these studies provided experimentally defined No-Observed-Adverse-Effect Levels (NOAELs) of 0.06% (approximately 50 mg/kg/day) for F2 offspring survival and 0.8% (approximately 600 mg/kg/day) for fertility, other measures of reproductive function, and developmental landmarks. Statistical evaluation of the data from both studies identified 108 mg/kg/day with a 95% lower bound value of 86 mg/kg/day as a theoretical NOAEL for reduced F2 offspring survival.

Skin sensitisation testing--new perspectives and recommendations.

Various methodological aspects of skin sensitisation testing have been explored, particularly in the context of animal welfare considerations and reliability and sensitivity of test methods. Recommendations are made for the conduct of current and proposed OECD skin sensitisation tests with respect to appropriate test configurations for the purposes of hazard identification and labelling, and the requirement for positive controls. Specifically, the following aspects of guinea pig sensitisation test methods have been addressed: (1) the number of test and control animals required; (2) the option of using joint positive controls between independent laboratories; (3) the choice of positive control chemicals; (4) the optimal conduct and interpretation of rechallenge; and (5) the requirement for pretreatment with sodium lauryl sulfate. In addition, the use of the murine local lymph node assay (LLNA) has been considered. A number of conclusions have been drawn and recommendations made as follows: In many instances, particularly with the conduct of the guinea pig maximisation test, it is acceptable to halve the number of test and control animals used. An optional scheme for the conduct of joint positive control studies within a co-ordinated group of laboratories is appropriate. Only one positive control chemical (alpha-hexyl cinnamic aldehyde) is necessary for the routine assessment of assay sensitivity. The proper conduct and interpretation of rechallenge can provide valuable information and confirmation of results in guinea pig sensitisation tests. Sodium lauryl sulfate should no longer be used as a pretreatment in the guinea pig maximisation test. The LLNA is a viable and complete alternative to traditional guinea pig test methods for the purposes of skin sensitisation hazard identification. These recommendations provide the opportunity for both animal welfare benefits and improved hazard identification.

Skin sensitization testing in potency and risk assessment.

The purpose of this article is to review, and make recommendations for, the use of relevant skin sensitization test methods, for the purposes of determination of relative potency and the threshold dose necessary for the induction of skin sensitization, and for risk assessment. In addressing the first area, the utility of three guinea pig tests (the guinea pig maximization test, the occluded patch test, and the open epicutaneous test) of the local lymph node assay (LLNA) and of human volunteer testing for the assessment of relative potency and identification of thresholds for sensitization were considered. The following conclusions were drawn. (1) Although attempts have been made to modify the guinea pig maximization test for the purposes of deriving dose-response relationships, this method is usually unsuitable for determination of relative sensitizing potency. (2) Guinea pig methods that do not require the use of adjuvant and which employ a relevant route of exposure (the occluded patch test and the open epicutaneous test) are more appropriate for the assessment of relative skin-sensitizing potency. (3) The LLNA is suitable for the determination of relative skin sensitizing potency, and the adaptation of this method for derivation of comparative criteria such as EC3 values (the estimated concentration of test chemical required to induce a stimulation index of 3 in the LLNA) provides an effective and quantitative basis for such measurements. (4) For all the methods identified above, potency is assessed relative to other chemical allergens of known skin sensitizing potential. The estimation of likely threshold concentrations is dependent upon the availability of suitable benchmark chemicals of known potency for human sensitization. (5) Human testing (and specifically, the Human Repeat Insult Patch Test) can provide information of value in confirming the absence of skin sensitizing activity of formulations and products under specific conditions of use and exposure. Based on the above, the following recommendations are made. (1) If results are already available from suitable guinea pig tests, then judicious interpretation of the data may provide information of value in assessing relative skin sensitizing potency. This option should be explored before other analyses are conducted. (2) The LLNA is the recommended method for new assessments of relative potency, and/or for the investigation of the influence of vehicle or formulation on skin sensitizing potency. (3) Whenever available, human skin sensitization data should be incorporated into an assessment of relative potency. With respect to risk assessment, the conclusion drawn is that all the available data on skin-sensitizing activity in animals and man should be integrated into the risk-assessment process. Appropriate interpretation of existing data from suitable guinea pig studies can provide valuable information with respect to potency, as the first step in the development of a risk assessment. However, for de novo investigations, the LLNA is the method favored for providing quantitative estimations of skin-sensitizing potency that are best suited to the risk assessment process. Finally, human testing is of value in the risk assessment process, but is performed only for the purposes of confirming product safety.

Neural mechanisms underlying migrating motor complex formation in mouse isolated colon.

1. Little is known about the intrinsic enteric reflex pathways associated with migrating motor complex (MMC) formation. Acetylcholine (ACh) mediates the rapid component of the MMC, however a non-cholinergic component also exists. The present study investigated the possible role of endogenous tachykinins (TKs) in the formation of colonic MMCs and the relative roles of excitatory and inhibitory pathways. 2. MMCs were recorded from the circular muscle at four sites (proximal, proximal-mid, mid-distal and distal) along the mouse colon using force transducers. 3. The tachykinin (NK(1) and NK(2)) receptor antagonists SR-140 333 (250 nM) and SR-48 968 (250 nM) reduced the amplitude of MMCs at all recording sites, preferentially abolishing the long duration contraction. Residual MMCs were abolished by the subsequent addition of atropine (1 microM). 4. The neuronal nitric oxide synthase inhibitor, N(omega)nitro-L-arginine (L-NOARG, 100 microM), increased MMC amplitude in the distal region, whilst reducing the amplitude in the proximal region. In preparations where MMCs did not migrate to the distal colon, addition of L-NOARG resulted in the formation of MMCs. Subsequent addition of apamin (250 nM) or suramin (100 microM) further increased MMC amplitude in the distal region, whilst suramin increased MMC amplitude in the mid-distal region. Apamin but not suramin reduced MMC amplitude in the proximal region. Subsequent addition of SR-140 333 and SR-48 968 reduced MMC amplitude at all sites. Residual MMCs were abolished by atropine (1 microM). 5. In conclusion, TKs, ACh, nitric oxide (NO) and ATP are involved in the neural mechanisms underlying the formation of MMCs in the mouse colon. Tachykinins mediate the long duration component of the MMC via NK(1) and NK(2) receptors. Inhibitory pathways may be involved in determining whether MMCs are formed.

Autoantibodies in primary Sjögren's syndrome: new insights into mechanisms of autoantibody diversification and disease pathogenesis.

Characterisation of autoantibodies and their target autoantigens in primary Sjögren's syndrome (SS) is an important entry point for studying this common systemic autoimmune disease. Diversification of anti-Ro/La responses is believed to occur by a process of determinant spreading following initiation of an autoimmune response to one component, possibly 52-kD Ro (Ro52). Recent evidence supports the ER-resident chaperone Grp78 as a potential candidate in the initiation of an autoimmune response against Ro52, by binding to a Grp78 binding motif in the COOH-terminal region of Ro52. The subsequent diversification of the anti-Ro/La response is influenced by distinct HLA class II alleles. Anti-salivary duct autoantibodies have been revisited and shown to be mimicked by cross-reactive isoantibodies to AB blood group antigens. Identification of autoantibodies that act as antagonists at M3-muscarinic receptors represents an important advance. As well as contributing to the sicca symptoms, the functional effects of these autoantibodies may explain associated features of autonomic dysfunction in patients with SS. Anti-M3 receptor autoantibodies occur in both primary and secondary SS and allow Sjögren's syndrome to be viewed as a disorder of anti-receptor autoimmunity.

Bacterial genomics as a potential tool for discovering new antimicrobial agents.

The past 30 years have witnessed the emergence of new infectious diseases as well as the re-emergence of those thought to be defeated or under control. It is likely that this threat will continue and that infectious micro-organisms will be found to be responsible for numerous diseases whose etiology had been previously unknown. Compounding this threat is the rapid evolution of drug resistance by micro-organisms that is rendering many existing antimicrobial agents obsolete. Thus, there is an urgent need for the development of new classes of antimicrobial agents and the identification of new drug targets. Over the past decade, advances in high-throughput automated DNA sequencing have delivered a wealth of genetic information in the form of whole genome sequences of microbial pathogens. Coupled with this advancement has been the development of new genetic tools and computational advances capable of selecting genes of particular interest as well as testing for the effects of candidate drugs. While no new drugs have yet been developed, further study into the application and limitations of these new approaches to the identification of novel targets will aid in overcoming the current problem of antimicrobial drug resistance.

Inhibitory effects of muscarinic receptor autoantibodies on parasympathetic neurotransmission in Sjögren's syndrome.

OBJECTIVE: Sjögren's syndrome (SS) is an autoimmune disorder characterized by dry eyes and mouth (sicca syndrome) and lymphocytic infiltration of the lacrimal and salivary glands. Abnormalities of parasympathetic neurotransmission may contribute to the glandular dysfunction. In this study, we used a functional assay to investigate autoantibody-mediated effects on parasympathetic neurotransmission and smooth muscle contraction. METHODS: Serum and purified IgG were obtained from patients with primary and secondary SS and from control subjects. Contraction of isolated bladder strips in response to stimulation of M3-muscarinic receptors by a muscarinic receptor agonist, carbachol, or by endogenous acetylcholine released from postganglionic parasympathetic nerves was measured before and after the addition of patient serum or IgG. RESULTS: Sera from 5 of 9 patients with primary SS and from 6 of 6 patients with secondary SS inhibited carbachol-evoked bladder contraction by approximately 50%. Sera from these patients also inhibited the action of neuronally released acetylcholine at M3-muscarinic receptors. Sera from 7 of 8 healthy individuals, from patients with rheumatoid arthritis without sicca symptoms, and from patients with systemic lupus erythematosus had no effect. The anti-muscarinic receptor activity was localized in the IgG fraction, since purified IgG from patients with SS also inhibited agonist- and nerve-evoked contractions. In this preliminary study, the autoantibodies seemed to be associated with the presence of bladder symptoms and other autonomic features. CONCLUSION: Autoantibodies that act as antagonists at M3-muscarinic receptors on smooth muscle occur in a subset of patients with primary and secondary SS. Their presence in secondary SS was unexpected and provides new evidence for a common pathogenetic link between primary and secondary SS. These autoantibodies appear to contribute to sicca symptoms and may explain associated features of autonomic dysfunction in some patients.